Voltage-gated sodium channels are critical determinants of neuronal and muscle cellular excitability. These channels may also play a crucial role in chronic pain, epilepsy and other neurological disorders. However, investigations into the precise functional role that specific sodium channel isoforms play in normal and abnormal cellular excitability is lacking. A main objective of our research is to identify molecular mechanism(s) underlying alterations in the electrical excitability of sensory neurons. Experimental and clinical studies have clearly shown that the peripheral nerve fibers, and the neuronal cell bodies that give rise to them, can become hyperexcitable after injury and that this hyperexcitability contributes to neuropathic pain. Changes in sodium currents are likely to alter the excitability of sensory neurons, and could contribute to the reduced threshold for repetitive firing and increased level of spontaneous firing that has been observed in injured and inflamed sensory neurons. Subthreshold sodium currents, currents that are active at membrane potentials negative to the threshold for action potential generation, can play crucial roles in regulating electrogenesis in neurons. The present proposal focuses on tetrodotoxin-sensitive subthreshold sodium currents in sensory neurons and their role in chronic pain mechanisms. This project will address the hypothesis that altered sodium currents play a crucial role in the development of enhanced excitability associated with chronic pain with the following specific aims: 1. Characterize the properties of sodium currents in cutaneous afferent dorsal root ganglion neurons acutely isolated from normal adult rats, after chronic peripheral inflammation and after peripheral nerve injury. 2. Determine how specific sodium channel isoforms contribute to sodium currents in control and sensitized neurons. 3. Examine the effect of sodium channel mutations that cause the inherited painful neuropathy primary erythermalgia in humans on Nav1.7 sodium channel properties and excitability in sensory neurons. Understanding the changes that occur in the sodium currents of sensory neurons following inflammation and/or nerve injury and how specific sodium channel isoforms contribute to these changes should enhance our understanding of the normal and abnormal physiology of sensory neurons and should aid the development of new therapeutic strategies for the treatment of pain.